The Effect of Circadian-Aligned Melatonin Supplementation on Pain and Hormonal Fluctuations in Women with Luteal Phase Dysfunction

Background & Objective: Luteal Phase Dysfunction (LPD) is characterized by inadequate progesterone secretion or action, often leading to infertility, early pregnancy loss, and cyclical symptoms. Melatonin, a circadian regulator with antioxidant properties, may enhance corpus luteum function when administered in a timing-specific manner. The present study was conducted with aim to evaluate the effect of circadian-aligned melatonin supplementation on luteal progesterone levels, ovulatory outcomes, pain, and symptom burden in women with LPD.Materials & Methods: This randomized, double-blind, placebo-controlled trial was conducted on 100 women aged 22-35 years with confirmed LPD who were allocated to receive either melatonin (3 mg) or placebo daily at 9:00 PM from cycle day 14-25 for three cycles. Primary outcomes included mid- (day 21) and late-luteal (day 24) serum progesterone concentrations; secondary outcomes comprised ovulation confirmation, pain (Visual Analogue Scale, VAS), and symptom burden (Daily Record of Severity of Problems, DRSP).Results: Baseline demographic and cycle characteristics were comparable between the two groups. By cycle 3, the melatonin group demonstrated significantly higher day 21 progesterone (median 9.85 ng/mL [IQR 9.66-13.40] vs. 8.78 [6.73–9.81], P<0.0001) and day 24 progesterone (mean±SD 11.15±3.47 ng/mL vs. 9.05±3.14 ng/mL, P=0.0021). A greater proportion exceeded the ≥10 ng/mL threshold on day 21 (32.0% vs. 10.0%, P=0.0141). DRSP luteal mean scores were significantly lower with melatonin (45.14±14.84 vs. 52.16±10.17, P=0.0071), indicating reduced symptom burden. No significant between-group differences were found in VAS pain scores or ≥30% pain reduction rates. Ovulation confirmation rates were similar in the two groups.Conclusion: Circadian-aligned melatonin supplementation significantly improved luteal progesterone profiles and reduced overall luteal-phase symptom severity in women with LPD, without a statistically significant effect on mean pain scores. These findings support melatonin’s potential as a low-risk, non-hormonal adjunct targeting both endocrine and symptomatic dimensions of LPD, meriting further investigation in fertility-focused trials.